Malignant gliomas remain one of the deadliest of all cancers despite maximal therapy. They present unique challenges to therapy with a median survival of 12 months. Simultaneous activation of several growth promoting and anti-apoptotic pathways represents the basis for the failure of monotherapies against this disease. In order to efficiently block growth of glioblastoma (GBM) cells, we have applied several combinatorial approaches. We have found that combination of histone deactylase inhibitors along with the glycolytic inhibitor 2-deoxyglucose (2DG) efficiently induced apoptosis in GBM cells. Furthermore, combination of the microtubule inhibitor patupilone and AEE788 –an inhibitor of EGFR, which is frequently activated in gliomas, induced apoptosis in GBM cells at doses that as single drugs were not effective. In GBM and other cancers, subpopulations of tumor cells with stem cell properties that are believed to constitute a tumor cell reservoir, have been identified. GBM cells frequently express the progenitor cell markers Nestin and Sox2 and low levels of the differentiation markers CNPase, GFAP and !-tubulin III. Bmi1 and Glycogen synthase kinase 3 (GSK3) has been implicated in stem cell maintenance, but how Bmi1 regulates differentiation is still unknown. We have identified a link between Bmi1 and GSK3 and showed that blocking GSK3 may be instrumental to reduce the GBM cancer stem cell pool. We found that the GSK3 inhibitors SB216763 as well as Lithium chloride depleted the cancer stem cell population in GBM cells and induced tumor cell differentiation, irrespective of the CD133 status. Cell proliferation and colony formation were markedly reduced in a dosedependent manner. Future work giving a deeper insight into the regulatory mechanisms of the receptor tyrosine kinases and downstream effectors will help us to identify more specific targets. Understanding the mechanisms why some targeted therapies work and others fail will finally bring us to the level that efficient long-term treatment strategies can be envisaged.